Solid forms of 2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1h-imidazol-4-ylethynyl]-pyridine

ABSTRACT

The present invention relates to the mono-sulfate salt, crystalline forms A and B of the mono-sulfate salt, an amorphous form of the mono-sulfate salt, hemi-sulfate salts, and a crystalline form A of the hemi-sulfate salt of the compound 2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/876,398, filed Dec. 21, 2006, which is hereby incorporated byreference in its entirety.

The present invention relates to mono-sulfate and hemi-sulfate salts of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine,to crystalline and amorphous forms thereof and to their use inpharmaceutical formulations.

2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinehas been already described in published PCT patent application No. WO2004/108701.

2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinehas been described as active on the mGluR5 receptor for the treatment ofdiseases, related to this receptor, such acute and/or chronicneurological disorders, in particular anxiety, or for the treatment ofchronic and acute pain, protection against liver damage, failure whetherdrug or disease induced, urinary incontinence, obesity, Fragile-X orAutism.

In a first aspect, the present invention relates to mono-sulfate saltand hemi-sulfate salts of the following compound:

-   2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

In another aspect, the present invention relates to two distinctcrystalline forms A and B of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

In yet another aspect, the present invention relates to the amorphousform of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

In still another aspect, the present invention relates to crystallineform A of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

The aforementioned salts and their crystalline and amorphous forms canbe distinguished by physical and chemical properties that can becharacterized by infrared spectra, X-ray powder diffraction patterns,melting behavior or glass transition temperatures.

The present invention also provides pharmaceutical compositionscontaining the abovementioned salts, crystalline or amorphous forms, anda pharmaceutically acceptable carrier.

In accordance with the invention the abovementioned salts, crystallineor amorphous forms can be used for the preparation of medicaments usefulin the control or prevention of illnesses based on the mGluR5 receptor.Such illnesses include acute and/or chronic neurological disorders, inparticular anxiety, or for the treatment of chronic and acute pain,protection against liver damage, failure whether drug or diseaseinduced, urinary incontinence, obesity, Fragile-X or Autism.

FIG. 1: shows an XRPD (X-Ray Powder Diffraction, STOE diffractometer)pattern of a typical lot of form A of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 2: shows an IR (InfraRed spectroscopy, Nicolet spectrometer)spectrum of a typical lot of form A of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 3: shows a TGA (Thermo Gravimetric Analysis, Mettler-Toledo system)curve of a typical lot of form A of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 4: shows an XRPD (X-Ray Powder Diffraction, Scintag diffractometer)pattern of a typical lot of form B of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 5: shows an IR (Infra Red spectroscopy, Mattson spectrometer)spectrum of a typical lot of form B of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 6: shows a TGA (Thermo Gravimetric Analysis, TA Instruments system)curve of a typical lot of form B of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine

FIG. 7: shows an XRPD (X-Ray Powder Diffraction, Scintag diffractometer)pattern of a typical lot of form A of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 8: shows an IR (Infra Red spectroscopy, Mattson spectrometer)spectrum of a typical lot of form A of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 9: shows a TGA (Thermo Gravimetric Analysis, TA Instruments system)curve of a typical lot of form A of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 10: shows an XRPD (X-Ray Powder Diffraction, STOE diffractometer)pattern of a typical lot of the amorphous form of the mono-sulfate saltof2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

FIG. 11: shows an IR (Infra Red spectroscopy, Nicolet spectrometer)spectrum of a typical lot of the amorphous form of the mono-sulfate saltof2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

As used herein, “Amorphous forms” denote a material that lacks longrange order and as such does not show sharp X-ray peaks. The XRPDpattern of an amorphous material is characterized by one or moreamorphous halos.

“Amorphous form of the mono-sulfate salt” is used herein as abbreviationof the amorphous form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

“API” is used herein as an acronym of active pharmaceutical ingredient.

“Form A of the mono-sulfate salt” is used herein as abbreviations forthe crystalline form A of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

“Form A of the hemi-sulfate salt” is used herein as abbreviations forthe crystalline form A of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

“Form B of the mono-sulfate salt” is used herein as abbreviations forthe crystalline form B of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

“Free base” is used herein as the abbreviation of the free base of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

“IPA” is used herein as an acronym of 2-propanol.

‘ACN’ is used herein as an acronym of acetonitrile.

“IR” is used herein as an acronym of Infra Red spectroscopy. IR spectrawere recorded as film of a Nujol suspension of approximately 5 mg ofsample and few Nujol between two sodium chloride plates, with an FTIRspectrometer in transmittance. The Spectrometer is a Nicolet™ 20SXB orequivalent (resolution 2 cm⁻¹, 32 or more coadded scans, MCT detector).

Alternatively, IR was recorded as KBr disc with approximately 0.6 mg ofsample and 160 mg of KBr. In this case, the Spectrometer is a MattsonGalaxy 5000 FTIR system (resolution 2 cm⁻¹, 32 or more coadded scans).

“Pharmaceutically acceptable” such as pharmaceutically acceptablecarrier, excipient, preservatives, solubilizers, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavoring agents, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants,etc., means pharmacologically acceptable and substantially non-toxic tothe subject to which the particular compound is administered.

“XRPD” is used herein as an acronym of X-Ray Powder Diffraction. X-raydiffraction patterns were recorded at ambient conditions in transmissiongeometry with a STOE STADI P diffractometer (Cu Kα radiation, primarymonochromator, position sensitive detector, angular range 3° to 42° 2Theta, approximately 60 minutes total measurement time). The sampleswere prepared and analyzed without further processing (e.g. grinding orsieving) of the substance.

Alternatively, X-ray diffraction patterns were measured on a Scintag X1powder X-ray diffractometer equipped with a sealed copper Kα1 radiationsource. The samples were scanned from 2° to 36° 2θ at a rate of 1° perminute with incident beam slit widths of 2 and 4 mm and diffracted beamslit widths of 0.3 and 0.2 mm.

For single crystal structure analysis a single crystal was mounted in aloop on a goniometer and measured at ambient conditions. Alternatively,the crystal was cooled in a nitrogen stream during measurement. Datawere collected on a STOE Imaging Plate Diffraction System (IPDS) fromSTOE (Darmstadt). In this case Mo-radiation of 0.71 Å wavelength wasused for data collection. Data was processed with STOE IPDS-software.The crystal structure was solved and refined with standardcrystallographic software. In this case the program ShelXTL from BrukerAXS (Karlsruhe) was used.

Alternatively, single crystal X-ray diffraction intensity data weremeasured at ambient conditions on a Bruker SMART APEX™ diffractometer(Mo Kα radiation, λ=0.71 Å). Raw area detector data frame integrationwas performed with the following softwares: SMART™ Version 5.630,SAINT™+Version 6.45 and SADABS™ Version 2.10. Bruker Analytical X-raySystems, Inc., Madison, Wis., USA, 2003. Direct methods structuresolution, difference Fourier calculations and full-matrix least-squaresrefinement against F² were performed according to Sheldrick, G. M.SHELXTL™ Version 6.14; Bruker Analytical X-ray Systems, Inc., Madison,Wis., USA, 2000.

“TGA” is used herein as an acronym of ThermoGravimetric Analysis. TGAcurves were measured on a Mettler-Toledo™ thermogravimetric analyzer(TGA850/SDTA). System suitability tests and calibrations were carriedout according to the internal standard operation procedure.

For the thermogravimetric analyses, approx. 5-10 mg of sample wereplaced in aluminum pans, accurately weighed and hermetically closed withperforation lids. Prior to measurement, the lids were automaticallypierced resulting in approx. 1.5 mm pin holes. The samples were thenheated under a flow of nitrogen of about 50 mL/min using a heating rateof 5 K/min up to 280° C.

Alternatively, thermogravimetric analysis was conducted using a Hi-Res2950 TGA from TA Instruments. The heating rate was 10° C./min with anitrogen purge maintained throughout the run.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

Pharmaceutical compositions of the invention, in addition to one of thesalts, crystalline or amorphous forms according to the inventionmentioned hereinabove, can contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragees and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the solutionsinclude, for example, water, polyols, sucrose, invert sugar, glucose,and the like

The preparation of the free base2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinehas been already described in published PCT patent applications Nos. WO2004/108701, the content of which is incorporated by reference herein.

As already mentioned hereinabove, the present invention relates to novelsalts and to crystalline and an amorphous form of these salts of thefollowing compound:

-   2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

It has been found that2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecan be isolated, depending upon the method of preparation, as amono-sulfate or as a hemi-sulfate salt.

Form A and form B of the mono-sulfate salt as well as an amorphous formcan be isolated from the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

Form A of the hemi-sulfate salt can be obtained for the hemi-sulfatesalt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

The mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecan be prepared by salt formation of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinewith sulfuric acid in 2-propanol with subsequent spontaneousprecipitation.

Form A of the mono-sulfate salt of the2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineis a solvent-free, crystalline form.

Form A of the mono-sulfate salt can be obtained by salt formation of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinewith sulfuric acid in 2-propanol with subsequent spontaneousprecipitation or by re-crystallization of form A of the mono-sulfatesalt in solvents comprising but not limited to ACN, ACN/water, methanol,ethanol, IPA, acetic acid, 1-octanol, IPA/49% sulfuric acid (10:1, v/v).

Form A of the mono-sulfate salt can be characterized by at least threepeaks selected from the following X-ray diffraction peaks obtained witha Cu_(Kα) radiation at 2θ (2 Theta)=9.8, 13.4, 14.2, 18.1, 18.9, 19.6,22.6, 22.9, 25.7, 27.1 and 29.9 (±0.2°).

Form A of the mono-sulfate salt can also be characterized by thefollowing X-ray diffraction peaks obtained with a Cu_(Kα) radiation at2θ (2 Theta)=9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1and 29.9 (±0.2°).

Form A of the mono-sulfate salt can also be characterized by the X-raypowder diffraction pattern shown on FIG. 1.

Form A of the mono-sulfate salt can also be characterized by an infraredspectrum having sharp bands at 3068, 2730, 2618, 2236, 2213, 1628, 1587,1569, 1518, 1384, 1374, 1295, 1236, 1168, 1157, 1116, 1064, 1019, 902,855, 786 and 674 cm⁻¹ (±3 cm⁻¹).

Form A of the mono-sulfate salt can also be characterized by theinfrared spectrum shown on FIG. 2.

Form A of the mono-sulfate salt is a solvent-free form as no significantweight loss is observed in the TGA curve prior to decomposition as shownon FIG. 3.

As already mentioned hereinabove, all these characteristics are shown onFIGS. 1 to 3 hereinafter.

A single crystal X-ray analysis of form A of the mono-sulfate salt wasconducted. Table 1 lists as an example some crystal structure data.Crystal form A of the mono-sulfate salt was found to be an anhydrateform of mono-sulfate salt as determined by single crystal analysis. Theexperimental XRPD pattern collected with the form A of the mono-sulfatesalt obtained is in excellent agreement with the simulated patterncalculated with atomic coordinates from single crystalline structureanalysis, indicating that form A of the mono-sulfate salt was a purecrystalline phase. In the structure of form A of the mono-sulfate salt,the fluoro-benzene ring is almost perpendicular to the imidazole ring asindicated by a dihedral angle of 90.7°. A hydroxyl group of a bisulfateanion forms an intermolecular hydrogen bond with an oxygen atom of aneighboring bisulfate anion. This bisulfate anion also serves as ahydrogen bond acceptor from a protonated imidazole nitrogen atom.

TABLE 1 crystal structure data of form A of the mono-sulfate salt NameForm A of the mono-sulfate salt Temperature 293(2) K Crystal system,space group Triclinic, P-1 Unit cell dimensions a = 9.996(2) Å α =98.60(3)° b = 9.996(2) Å β = 98.97(3)° c = 11.287(2) Å γ = 112.49(3)°Cell volume 1001.9(3) Å³ Molecules in unit cell 2 Density (calculated)1.398 g/cm³

Form B of the mono-sulfate salt is a mono-hydrate crystalline form.

Form B of the mono-sulfate salt can be obtained by solvent equilibrationof form A of the mono-sulfate salt in IPA/water (e.g. 3:1 v/v). Form Bof the mono-sulfate salt can also be prepared by re-crystallization ofform A of the mono-sulfate salt in IPA/water (e.g. 3:1 v/v). Form B ofthe mono-sulfate salt can further be obtained upon digestion of form Aof the mono-sulfate salt in e.g. aqueous sulfuric acid.

Form B of the mono-sulfate salt can be characterized by at least threepeaks selected from the following X-ray diffraction peaks obtained witha Cu_(Kα) radiation at 2θ (2 Theta)=8.9, 10.2, 14.3, 14.7, 15.4, 17.1,18.8, 19.5, 20.9, 22.5 and 23.8 (±0.2°).

Form B of the mono-sulfate salt can also be characterized by thefollowing X-ray diffraction peaks obtained with a Cu_(Kα) radiation at2θ (2 Theta)=8.9, 10.2, 14.3, 14.7, 15.4, 17.1, 18.8, 19.5, 20.9, 22.5and 23.8 (±0.2θ).

Form B of the mono-sulfate salt can also be characterized by the X-raypowder diffraction pattern shown on FIG. 4.

Form B of the mono-sulfate salt can also be characterized by an infraredspectrum having sharp bands at 3122, 3039, 3003, 2923, 2853, 2719, 2608,2231, 1622, 1585, 1565, 1515, 1439, 1373, 1346, 1224, 1158, 1116, 1082,1047, 1015, 987, 901, 787, and 673 (±3 cm⁻¹).

Form B of the mono-sulfate salt can also be characterized by theinfrared spectrum shown on FIG. 5.

Form B of the mono-sulfate salt is a monohydrate with a correspondingweight loss in the TGA curve as shown on FIG. 6.

As mentioned hereinabove, all these characteristics are shown on FIGS. 4to 6 hereinafter.

A room temperature single crystal X-ray analysis of form B of themono-sulfate salt was conducted. As an example table 2 lists somecrystal structure data.

Form B of the mono-sulfate salt was found to be a mono-hydrate of themono-sulfate salt as determined by single crystal analysis. Theexperimental XRPD pattern collected with the form B of the mono-sulfatesalt obtained is in excellent agreement with the simulated patterncalculated with atomic coordinates from single crystal structureanalysis, indicating that form B of the mono-sulfate salt was a purecrystalline phase. In the structure of form B of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine,the dihedral angle between the fluoro-benzene ring and the imidazolering was found to be approximately 77.3°. The protonated imidazolenitrogen atom forms an intermolecular hydrogen bond with a bisulfateanion. At the same time, the bisulfate anion is also involved inhydrogen bonding networks with a chloro-pyridine nitrogen atom and awater molecule.

TABLE 2 Crystal structure data and structure refinement for form B ofthe mono-sulfate salt Name Form B of the mono-sulfate salt Temperature294(2) K Crystal system, Space group Triclinic, P-1 Unit cell dimensionsa = 8.9686(5) Å α = 107.0630(10)° b = 10.6790(6) Å β = 100.1590(10)°. c= 10.9563(6) Å γ = 96.6930(10)° Cell volume 971.51(9) Å³ molecules inunit cell 2 Density (calculated) 1.510 g/cm³

The amorphous form of mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecan be obtained from a methanol solution upon fast evaporation at about65° C. under vacuum.

The amorphous form of mono-sulfate salt can be characterized by the lackof sharp X-ray diffraction peaks in its XRPD pattern; and/or an infraredspectrum having sharp bands at 2730, 2592, 2219, 1633, 1586, 1570, 1513,1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712and 670 cm⁻¹ (+3 cm⁻¹).

The amorphous form of mono-sulfate salt can also be characterized by theinfrared spectrum shown on FIG. 11.

As mentioned hereinabove, all these characteristics are shown on FIGS.10 to 11 hereinafter.

The hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecan be prepared by solvent equilibration of form A of the mono-sulfatesalt in water.

Form A of the hemi-sulfate salt can be obtained by solvent equilibrationof form A of the mono-sulfate salt in water. It can also be prepared byre-crystallization or digestion of form A of the mono-sulfate salt insolvent systems comprising but not limited to water, water/methanol(e.g. 4:1, v/v), water/ethanol (e.g. 4:1, v/v), water/2-propanol (e.g.3:1, v/v).

Form A of the hemi-sulfate salt is a crystalline hemi-hydrate form ofthe following salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinewith sulfuric acid (2:1) (hemi sulfate salt of the2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinefree base):

Form of the hemi-sulfate salt can be characterized by at least threepeaks selected from the following X-ray diffraction peaks obtained witha Cu_(Kα) radiation at 2θ (2 Theta)=7.4, 8.9, 11.0, 11.8, 12.8, 15.8,17.3, 18.1, 19.8, 25.0 and 26.2 (±0.2°).

Form of the hemi-sulfate salt can also be characterized by the followingX-ray diffraction peaks obtained with a Cu_(Kα) radiation at 20 (2Theta)=7.4, 8.9, 11.0, 11.8, 12.8, 15.8, 17.3, 18.1, 19.8, 25.0 and 26.2(±0.2°).

Form of the hemi-sulfate salt can also be characterized by the X-raypowder diffraction pattern shown on FIG. 7.

Form of the hemi-sulfate salt can also be characterized by an infraredspectrum having sharp bands at 3364, 3075, 3004, 2922, 2851, 2717, 2208,1658, 1632, 1585, 1567, 1514, 1413, 1372, 1159, 1122, 1038, 986, 902,846, 821, 788, 721, 712, and 668 (±3 cm⁻¹).

Form of the hemi-sulfate salt can also be characterized by the infraredspectrum shown on FIG. 8.

Form A of the hemi-sulfate salt is a hemi-hydrate with a correspondingweight loss in the TGA curve as shown on FIG. 9.

As already mentioned hereinabove, all these characteristics are shown onFIGS. 7 to 9 hereinafter.

A low and room temperature single crystal X-ray analysis of form A ofthe hemi-sulfate salt was conducted. Table 3 lists as an example somecrystal structure data.

Form A of the hemi-sulfate salt was found to be a hemi-hydrate of thehemisulfate as determined by single crystal structure analysis. In thestructure of form A of the hemi-sulfate salt, there are two APImolecules in the asymmetric unit. The experimental XRPD patterncollected was consistent with the simulated pattern calculated withatomic coordinates from single crystal structure analysis, indicating apure crystalline phase. The conformations of these two API molecules areslightly different as indicated by the dihedral angle differencesbetween the fluoro-benzene ring and the imidazole ring (approximately70° vs approximately 61°); however, in both molecules, thechloro-pyridine rings are almost co-planer to the imidazole ring asdemonstrated by very small dihedral angles (approximately 5° vsapproximately 6°). The protonated imidazole nitrogen atoms formintermolecular hydrogen bonds with a sulfate anion and a water molecule.At the same time, the water molecule is also involved in hydrogenbonding with two sulfate anions.

TABLE 3 Crystal structure data and structure refinement for form A ofthe hemi-sulfate salt Name Form A of the hemi-sulfate salt Temperature294(2) K Crystal system, Space group Monoclinic, C2/c Unit celldimensions a = 18.3260(13) Å α = 90° b = 17.0770(12) Å β = 109.002(1)° c= 25.1530(18) Å γ = 90° Cell volume 7442.8(9) Å³ molecules in unit cell8 Density (calculated) 1.370 Mg/m³

The salt can be formulated at low or high concentrations in acomposition further comprising usual pharmaceutically acceptableadjuvants known in the art.

The present invention also provides pharmaceutical compositionscontaining one or more of the following species:

-   a mono- or hemi-sulfate salt of    2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;-   form A or B of the mono-sulfate salt of    2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;-   form A of the hemi-sulfate salt of    2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine;-   the amorphous form of    2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.    and a pharmaceutically acceptable carrier.

These pharmaceutical compositions can be in the form of tablets, coatedtablets, dragees, hard and soft gelatine capsules, solutions, emulsionsor suspensions. The invention also provides a process for the productionof such compositions, which comprises bringing the aforementionedmodifications and forms into a galenical administration form togetherwith one or more therapeutically inert carriers.

In addition, the pharmaceutical compositions can containpharmaceutically acceptable preservatives, solubilizers, stabilizers,wetting agents, emulsifiers, sweeteners, colorants, flavoring agents,salts for varying the osmotic pressure, buffers, masking agents orantioxidants. They can also contain still other therapeutically valuablesubstances.

In accordance with the invention, the salts, crystalline or amorphousforms according to the invention mentioned hereinabove can be used forthe preparation of medicaments useful in the treatment or prevention ofillnesses in which the mGluR5 receptors play a role. Such illnessesinclude acute and/or chronic neurological disorders, in particularanxiety, or for the treatment of chronic and acute pain, protectionagainst liver damage, failure whether drug or disease induced, urinaryincontinence, obesity, Fragile-X or Autism.

The salts and crystalline and amorphous forms of the compounds of theinvention can be used in method of treating an illness selected from thegroup consisting of acute and/or chronic neurological disorders, inparticular anxiety, or for the treatment of chronic and acute pain,protection against liver damage, failure whether drug or diseaseinduced, urinary incontinence, obesity, Fragile-X or Autism, whichmethod comprises administering to an individual an effective amount ofone species selected from the group consisting of the salts, crystallineor amorphous forms according to the invention mentioned hereinabove.

The dosage at which the salts, crystalline or amorphous forms accordingto the invention are administered can vary within wide limits and will,of course, have to be adjusted to the individual requirements in eachparticular case. In the case of oral administration the dosage foradults can vary from about 0.01 mg to about 1000 mg, preferably fromabout 0.05 mg to about 20 mg, and still more preferably from about 0.5mg to about 5 mg per day. The daily dosage may be administered as singledose or in divided doses and, in addition, the upper limit can also beexceeded when this is found to be indicated.

EXAMPLE 1 Preparation of form A of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineGeneral

Form A of the mono-sulfate salt of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecan be formed upon salt formation with or without seeding with form A ofthe mono-sulfate salt in an appropriate solvent system as e.g.2-propanol/water, or by re-crystallization of form A of the mono-sulfatesalt in solvents comprising but not limited to acetonitrile,acetonitrile/water, methanol, ethanol, 2-propanol, acetic acid,1-octanol, 2-propanol/49% sulfuric acid (10:1, v/v).

Preparation Procedure

61.0 g of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinewas dissolved in 610 mL of 2-propanol. The solution was filtered and thefilter rinsed with 31 mL of 2-propanol. To the combined solutions amixture of 30 mL of water and 18.91 g of sulfuric acid (97%) was addeddrop-wise. The solution was cooled to 0-5° C. Seeding was performed at58° C. as needed. The solid residues were filtered, washed with2-propanol (0-5° C.) and dried at 50° C./<1 mbar for 18 h. Yield: 69.1 g(87.1%).

Form A seeding crystals can be prepared upon cooling crystallization ofa hot solution of 250 mg of the mono-sulfate salt of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinein 10 ml of 2-propanol. After cooling to 0° C. the solid residues can befiltered and dried at 50° C. under vacuum.

Solid State Properties of Form A of the Mono-Sulfate Salt

XRPD-pattern, IR-spectrum and TGA-curve of a typical lot of form A ofthe mono-sulfate salt are listed in FIGS. 1 to 3.

EXAMPLE 2 Preparation of form B of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineGeneral

Form B of the mono-sulfate salt of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecan be produced by solvent equilibration of form A of the mono-sulfatesalt in solvent systems as e.g. 2-propanol/water or 1 N sulfuric acid,or upon seeded cooling crystallization of the mono-sulfate salt of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinein solvent systems as e.g. 2-propanol/water.

Preparation Procedure

300 mg of form A of the mono-sulfate salt of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinewas dissolved in 3 ml 2-propanol and 1 ml water at 60° C. to produce aclear solution. The clear solution was seeded with form B of themono-sulfate salt and sealed at room temperature. Single crystals wereformed after 3 days.

Seeding crystals can be prepared by formation of a saturated slurry ofform A of the mono-sulfate salt of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinein 2-propanol and water (3:1 v/v) at room temperature. The slurry wasstirred at room temperature for approximately 3 weeks. The solids werefiltered via a glass filter to afford crystalline form B of themono-sulfate salt as a wet cake.

Solid State Properties of Form B of the Mono-Sulfate Salt

XRPD-pattern, IR-spectrum and TGA-curve of a typical lot of form B ofthe mono-sulfate salt are listed in FIGS. 4 to 6.

EXAMPLE 3 Preparation of form A of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineGeneral

Form A of the hemi-sulfate salt of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecan be produced by solvent equilibration of form A of the mono-sulfatesalt in solvents as e.g. water. It can also be prepared byre-crystallization or digestion of form A of the mono-sulfate salt insolvent systems comprising but not limited to water, water/methanol(e.g. 4:1, v/v), water/ethanol (e.g. 4:1, v/v), water/2-propanol (e.g.3:1, v/v).

Preparation Procedure

41 g of form A of the mono-sulfate of2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinewas mixed with 128 g of water. The slurry was stirred at roomtemperature for 2-16 h. After all the form A of the mono-sulfate salthad been converted to the hemi sulfate salt the crystals were collectedby filtration and rinsed with water. The wet cake was dried at 40° C. ina vacuum oven for 48 hrs. The yield was ˜93%.

Solid State Properties of Form A of the Hemi-Sulfate Salt

XRPD-pattern, IR-spectrum and TGA-curve of a typical lot of form A ofthe hemi-sulfate salt are listed in FIGS. 7 to 9.

EXAMPLE 4 Preparation of the amorphous form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineFormation of the Amorphous Form

Amorphous mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineis accessible upon fast evaporation of a solution in an a appropriatesolvent, preferably methanol.

Fast Evaporation

0.53 g of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinewas dissolved in 10 mL of methanol at approximately 65° C. Aftercomplete evaporation of the solvent under vacuum, the solid (foam) wasfurther dried at ca. 50° C./5-20 mbar for 18 h. Analysis revealedamorphous2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.

Solid State Properties of the Amorphous Form

XRPD-pattern and IR-spectrum of the amorphous form are listed in FIGS.10 to 11.

Formulation

Capsule Formulation (Wet granulation) mg/capsule Item Ingredients 0.05mg 0.5 mg 2.0 mg 20.0 mg 1. Form A of monosulfate salt 0.065 0.650 2.60226.02 2. Lactose Monohydrate 108.934 109.349 107.398 83.98 3. StarchMaize Partially 60.00 60.00 60.00 60.00 Pregelatinized (type 1500) 4.Croscarmellose Sodium 8.00 8.00 8.00 8.00 5. Povidone 30 15.00 15.0015.00 15.00 6. Sodium lauryl sulfate 1.00 — — — 7. Talc 6.00 6.00 6.006.00 8. Magnesium Stearate 1.00 1.00 1.00 1.00 Total 200.00 200.00200.00 200.00

Manufacturing Procedure

1. Mix items 1, 2, 3, 4, 5 and 6 in a suitable mixer for 30 minutes.2. Add items 7 and 8 and mix for 3 minutes.3. Fill into a suitable capsule.

1. A mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.2. A hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine.3. A crystalline form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by at least three peaks selected from the following X-raydiffraction peaks obtained with a Cu_(Kα) radiation at 2θ (2 Theta)=9.8,13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1 and 29.9 (±0.2θ).4. A crystalline form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized the following X-ray diffraction peaks obtained with aCu_(Kα) radiation at 2θ (2 Theta)=9.8, 13.4, 14.2, 18.1, 18.9, 19.6,22.6, 22.9, 25.7, 27.1 and 29.9 (±0.2θ).
 5. A crystalline form of themono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by the X-ray powder diffraction pattern shown on FIG. 1.6. A crystalline form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineaccording to claim 1 characterized by an infrared spectrum having sharpbands at 3068, 2730, 2618, 2236, 2213, 1628, 1587, 1569, 1518, 1384,1374, 1295, 1236, 1168, 1157, 1116, 1064, 1019, 902, 855, 786 and 674cm⁻¹ (±3 cm⁻¹)
 7. A crystalline form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineaccording to claim 1 characterized by the infrared spectrum shown onFIG.
 2. 8. A crystalline form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by at least three peaks selected from the following X-raydiffraction peaks obtained with a Cu_(Kα) radiation at 2θ (2 Theta)=8.9,10.2, 14.3, 14.7, 15.4, 17.1, 18.8, 19.5, 20.9, 22.5 and 23.8 (±0.2°).9. A crystalline form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by the following X-ray diffraction peaks obtained with aCu_(Kα) radiation at 2θ (2 Theta)=8.9, 10.2, 14.3, 14.7, 15.4, 17.1,18.8, 19.5, 20.9, 22.5 and 23.8 (±0.2°).
 10. A crystalline form of themono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by the X-ray powder diffraction pattern shown on FIG. 4.11. A crystalline form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineaccording to claim 1 characterized by an infrared spectrum having sharpbands at 3122, 3039, 3003, 2923, 2853, 2719, 2608, 2231, 1622, 1585,1565, 1515, 1439, 1373, 1346, 1224, 1158, 1116, 1082, 1047, 1015, 987,901, 787, and 673 (+3 cm⁻¹).
 12. A crystalline form of the mono-sulfatesalt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineaccording to claim 1 characterized by the infrared spectrum shown onFIG.
 5. 13. A crystalline form of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by at least three peaks selected from the following X-raydiffraction peaks obtained with a Cu_(Kα) radiation at 2θ (2 Theta)=7.4,8.9, 11.0, 11.8, 12.8, 15.8, 17.3, 18.1, 19.8, 25.0 and 26.2 (±0.2°).14. A crystalline form of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by the following X-ray diffraction peaks obtained with aCu_(Kα) radiation at 2θ (2 Theta)=7.4, 8.9, 11.0, 11.8, 12.8, 15.8,17.3, 18.1, 19.8, 25.0 and 26.2 (±0.2°).
 15. A crystalline form of thehemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by the X-ray powder diffraction pattern shown on FIG. 7.16. A crystalline form of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineaccording to claim 2 characterized by an infrared spectrum having sharpbands at 3364, 3075, 2717, 2577, 2234, 2208, 1568, 1632, 1585, 1567,1514, 1468, 1413, 1372, 1222, 1159, 1084, 1038, 986, 902, 846, 788 712,668 and 620 (+3 cm⁻¹)
 17. A crystalline form of the hemi-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridineaccording to claim 1 characterized by the infrared spectrum shown onFIG.
 8. 18. An amorphous form of the mono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by an absence of sharp X-ray peaks in its XRPD patternand/or an infrared spectrum having sharp bands at 2730, 2592, 2219,1633, 1586, 1570, 1513, 1375, 1226, 1157, 1130, 1115, 1084, 1040, 986,903, 848, 788, 712 and 670 cm⁻¹ (±3 cm⁻¹).
 19. An amorphous form of themono-sulfate salt of2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridinecharacterized by the infrared spectrum shown on FIG.
 11. 20. Apharmaceutically acceptable composition comprising a salt according toclaim 1 or a crystalline form or an amorphous form thereof and one ormore pharmaceutically acceptable carriers.